The objective of this K08 proposal is to provide Dr. Lewina Lee with the necessary expertise to launch an independent research career investigating the interplay of biological, psychosocial, and behavioral factors that underlie the association between stress and health over age. A mentoring team, led by Avron Spiro, Ph.D. (Boston University; BU), Laura Kubzansky, Ph.D. (Harvard University), and David Almeida (Pennsylvania State University; PSU), with assistance from several consultants, will guide Dr. Lee in conducting the proposed research and training activities. Building on Dr. Lee's background in clinical aging and quantitative methodology, the Training Plan will allow her to: (1) obtain training in the physiology of human stress response; (2) advance her knowledge of pathophysiologic processes that underlie age-related diseases; and (3) gain skills to lead an independent research program. Key training activities include formal coursework and didactics; mentorship from interdisciplinary experts; hands-on training in study design, data collection and analysis; and conference attendance. Training will take place at BU and PSU. Training activities are augmented by implementing a mentored Research Plan. The goal of the proposed research is to examine abnormal acute stress response and multisystem physiologic dysregulation as mechanisms that explain the negative effects of cumulative psychosocial stress exposure on cardiovascular disease and premature mortality. The Specific Aims are to: (1) examine acute stress response as a mediator of the association between cumulative psychosocial stress exposure and multisystem physiologic dysregulation; and (2) examine age trajectories of physiological functioning over 2 decades as mediators of the association between cumulative psychosocial stress exposure and later-life health. These aims will be addressed by analyzing multi-modal data from the nationally representative Midlife in the United States study and longitudinal data from the VA Normative Aging Study using structural equation models. The significance of the proposed research lies in: (a) a more precise understanding of the biological mechanisms by which the cumulative impact of psychosocial stress exposure gets under the skin to affect physical health across the lifespan, and (b) the identification of a risky profile of acute stress response that signals early risk for stress-related negative health outcomes. This project directly addresses NIA's strategic direction (A-1) on discovering causes and risk factors associated with disease and disability in older adults. Findings are expected to inform the development of interventions to reduce disease burden in later life (strategic direction B-1). This award will equip Dr. Lee with in-depth knowledge and skills to lead an independent and interdisciplinary research program to investigate the mechanistic links between stress and health across the lifespan.